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AF4/FEL, a gene involved in infant leukemia: sequence variations, gene structure, and possible homology with a
J L Frestedt1, J M Hilden, J H Kersey
1Department of Laboratory Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Insights
The AF4 gene, implicated in infant acute lymphoblastic leukemia, was sequenced, revealing its genomic structure and variations. Homologous regions were found on chromosome 5q31, a site also linked to MLL gene rearrangements in leukemia.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The t(4;11) translocation is a common chromosomal abnormality in infant acute lymphoblastic leukemia (ALL), associated with a poor prognosis.
- This translocation fuses the MLL gene (11q23) with the AF4 gene (4q21), creating chimeric transcripts potentially driving leukemogenesis.
- The function of the AF4 gene remains largely unknown.
Purpose of the Study:
- To characterize the AF4 gene, including its cDNA sequence and genomic structure.
- To identify potential functional insights into AF4 by searching for homologous sequences in the human genome.
- To explore potential links between AF4 and MLL gene rearrangements in leukemia.
Main Methods:
- Sequencing of AF4 cDNA from human placental tissue.
- Identification of intron-exon boundaries in the AF4 genomic structure.
- Bioinformatic analysis of GenBank sequences for homology to AF4 protein.
Main Results:
- Detailed cDNA sequence information for AF4 was obtained, with high expression in placental tissue.
- Six intron-exon boundaries of the AF4 gene were identified.
- Three homologous regions with varying amino acid identity (32-50%) were found between AF4 and sequences in the chromosome 5q31 interleukin-growth hormone cluster.
- The 5q31 region is also implicated in MLL gene rearrangements in leukemia.
Conclusions:
- The study provides foundational sequence and genomic structure data for the AF4 gene.
- Homology to a region on chromosome 5q31 suggests potential functional roles for AF4 and a shared genomic context with MLL rearrangements in leukemia.
Abstract:
The most common chromosome abnormality among infants with acute lymphoblastic leukemia is a t(4;11)(q2l;q23) and patients with this 4;11 translocation have a very poor prognosis. This unique genetic rearrangement fuses the MLL/ALL-1/HRX-Htrx gene at 11q23 with the AF4/FEL gene at 4q21. The resulting chimeric mRNAs presumably encode chimeric proteins which contribute to the leukemogenic state. The AF4 gene remains poorly understood with an unknown function. In this report, we describe the cDNA sequence information from human placental tissue where AF4 mRNA is highly expressed. We identified six intron-exon boundaries in the AF4 genomic structure and discussed more than 30 AF4 cDNA sequence variations reported in the literature. In addition, we identified three overlapping genomic sequences in GenBank entitled the "interleukin growth hormone cluster on chromosome 5q31," which, when aligned and translated, had three regions that suggested homology to the predicted AF4 protein sequence (32% amino acid sequence identity over 314 amino acids, 43% over 63 amino acids, and 50% over 40 amino acids). Of interest, this same chromosome 5q31 region has also been implicated in MLL gene rearrangements in human leukemia.